Researchers successfully 3D-print biomimetic liver tissue for drug screening.


The liver plays a critical role in how the body metabolizes drugs and produces key proteins. This is why liver models are increasingly being developed in the lab as platforms for drug screening. However, existing models so far lack both the complex micro-architecture and diverse cell makeup of a real liver.  Now, researchers at the University of California, San Diego have 3D-printed a tissue that closely mimics the human liver’s sophisticated structure and function. The team state that their new model could be used for patient-specific drug screening and disease modeling, saving time and money when developing new drugs.  The opensource study is published in the journal Proceedings of the National Academy of Sciences.

Previous studies show that the liver is unique in that it receives a dual blood supply with different pressures and chemical constituents.  The failure of these functions is closely related to disease development and drug-induced toxicity. For these reasons, in vitro liver models have been extensively developed to serve as platforms for pathophysiological studies and as an alternative to animal models in drug screening and hepatotoxicity prediction.  However, human hepatocytes lose many liver-specific functions rapidly when cultured in vitro.  Consequently, hepatocytes derived from human-induced pluripotent stem cells with the potential to be patient specific, have been widely acknowledged as the most promising cell source for developing precision human hepatic models.  Although there are many reports on functional 2D cell differentiation, few studies have demonstrated the in vitro maturation of hiPSC-derived hepatic progenitor cells in a 3D environment that depicts the physiologically relevant cell combination and microarchitecture.  The current study engineers a human liver tissue model in 3D that more closely resembles the real thing, a diverse combination of liver cells and supporting cells systematically organized in a hexagonal pattern.

The current study employed a novel bioprinting technology which can rapidly produce complex 3D microstructures that mimic the sophisticated features found in biological tissues. The lab explain that the liver tissue was printed in two steps; first, they printed a honeycomb pattern of 900-micrometer-sized hexagons, each containing liver cells derived from human induced pluripotent stem cells.  In the next step, endothelial and mesenchymal supporting cells were printed in the spaces between the stem-cell-containing hexagons.  Results show that the entire structure, a 3 × 3 millimeter square, 200 micrometers thick, takes just seconds to print; a vast improvement over other methods to print liver models, which can take hours.  The researchers note that an advantage of human induced pluripotent stem cells is they are patient-specific and since these cells are derived from a patient’s skin cells, they didn’t need to extract cells from the liver.

The structure was cultured in vitro for at least 20 days, after which the team tested the resulting tissue’s ability to perform various liver functions, such as albumin secretion and urea production, and compared it to other models. Data findings show that their model was able to maintain these functions over a longer time period than other liver models. Results show that their model also expressed a relatively higher level of a key enzyme that’s considered to be involved in metabolizing many of the drugs administered to patients.

The team surmise that their model has the potential of reproducing this intricate blood supply system, thus providing unprecedented understanding of the complex coupling between circulation and metabolic functions of the liver in health and disease.  They go on to add that this will serve as a great drug screening tool for pharmaceutical companies, opening the door for patient-specific organ printing in the future.  For the future, the researchers state that the liver tissue constructed by this novel 3D printing technology will also be extremely useful in reproducing in vitro disease models such as hepatitis, cirrhosis, and cancer.

Source: University of California, San Diego

 

Images of the 3-D-printed parts of the biomimetic liver tissue include: liver cells derived from human induced pluripotent stem cells (left), endothelial and mesenchymal supporing cells (center), and the resulting organized combination of multiple cell types (right).  Credit: Chen Laboratory, UC San Diego.

Images of the 3-D-printed parts of the biomimetic liver tissue include: liver cells derived from human induced pluripotent stem cells (left), endothelial and mesenchymal supporing cells (center), and the resulting organized combination of multiple cell types (right). Credit: Chen Laboratory, UC San Diego.

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